U.S. patent application number 16/422467 was filed with the patent office on 2020-10-01 for oral composition and method.
The applicant listed for this patent is Kunming Lanchie Dental Hospital, Ltd., Kunming Yeshui Bio-Tech, LTD. Invention is credited to Kewang Lu, Yang Song, Yun Xu, Lei Zhang.
Application Number | 20200306344 16/422467 |
Document ID | / |
Family ID | 1000004261328 |
Filed Date | 2020-10-01 |
United States Patent
Application |
20200306344 |
Kind Code |
A1 |
Xu; Yun ; et al. |
October 1, 2020 |
ORAL COMPOSITION AND METHOD
Abstract
The present invention relates to oral composition and the method
of preparation and use of such composition for inhibiting,
reducing, and/or disrupting oral biofilm. The composition comprises
a stabilizing matrix, a cationic biocide, and a peroxide
source.
Inventors: |
Xu; Yun; (Kunming, CN)
; Zhang; Lei; (Kunming, CN) ; Song; Yang;
(Kunming, CN) ; Lu; Kewang; (Dover, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Kunming Lanchie Dental Hospital, Ltd.
Kunming Yeshui Bio-Tech, LTD |
Kunming
Kunming |
|
CN
CN |
|
|
Family ID: |
1000004261328 |
Appl. No.: |
16/422467 |
Filed: |
May 24, 2019 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 8/22 20130101; A61K
38/1729 20130101; A61K 33/40 20130101; A61K 8/8176 20130101; A61Q
11/00 20130101 |
International
Class: |
A61K 38/17 20060101
A61K038/17; A61K 8/22 20060101 A61K008/22; A61K 33/40 20060101
A61K033/40; A61K 8/81 20060101 A61K008/81 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 25, 2019 |
CN |
201910227205.6 |
Claims
1. An oral composition for inhibiting, reducing, and/or disrupting
an oral biofilm comprising (i) about 0.05% to about 0.2% of a
cationic biocide selected from the group consisting of a dual chain
quaternary ammonium biocide and a single chain quaternary ammonium
biocide, (ii) about 0.1% to about 2.0% of a compatible peroxide
source, and (iii) about 85% to about 99% of a stabilizing matrix,
wherein the percentages are based on the weight of the composition
and the percent of the peroxide source is calculated as a weight
percent equivalent as if the peroxide source were hydrogen
peroxide.
2. An oral composition according to claim 1, wherein the
stabilizing matrix comprises a carrier, a thickening system, and
optionally further includes one or more compatible adjuvants.
3. The oral composition according to claim 2, wherein the carrier
is polyhydric alcohol.
4. The oral composition according to claim 3, wherein the
polyhydric alcohol is propylene glycol and is present in amounts of
about 40% to about 90%, wherein the percentages are based on the
weight of the composition.
5. The oral composition according to claim 4, having about 75% to
about 85% propylene glycol.
6. The oral composition according to claim 2, wherein the
thickening system comprises polyvinyl pyrrolidone.
7. The oral composition according to claim 6, comprising about 2%
to about 6% polyvinyl pyrrolidone, wherein the percentages are
based on the weight of the composition.
8. The oral composition according to claim 2, wherein the
thickening system comprises fumed silica.
9. The oral composition according to claim 8, wherein the fumed
silica is hydrophilic fumed silica and is present in amounts of
about 5% to about 11%, wherein the percentages are based on the
weight of the composition.
10. The oral composition according to claim 1, wherein the peroxide
source is carbamide peroxide.
11. The oral composition according to claim 1, wherein the dual
chain quaternary ammonium cationic biocide is proline, 5-oxo-,
ion(1-), N-decyl-N,N-dimethyl-1-decanaminium.
12. The oral composition according to claim 1, wherein the single
chain quaternary ammonium cationic biocide is hexadecylpyridinium
chloride.
13. The oral composition according to claim 1, where the cationic
biocide is proline, 5-oxo-, ion(1-),
N-decyl-N,N-dimethyl-1-decanaminium, the peroxide source is
carbamide peroxide, and the thickening system comprises propylene
glycol, polyvinylpyrrolidone, and hydrophilic fumed SiO.sub.2.
14. The oral composition according to claim 1, where the cationic
biocide is hexadecylpyridinium chloride, the peroxide source is
carbamide peroxide, and the thickening system comprises propylene
glycol, polyvinylpyrrolidone, and hydrophilic fumed SiO.sub.2.
15. An oral composition according to claim 1, where the thickening
system comprises a compatible foaming agent selected from the group
consisting of poloxamer or fatty acid polyoxyethylene ether.
16. An oral composition according to claim 15, where the compatible
foaming agent is poloxamer 188.
17. An oral composition according to claim 15, where the compatible
foaming agent is fatty alcohol polyoxyethylene ether 9.
18. An oral composition according to claim 13, where the thickening
system comprises a compatible foaming agent selected from the group
consisting of poloxamer or fatty acid polyoxyethylene ether.
19. An oral composition according to claim 14, where the thickening
system comprises a compatible foaming agent selected from the group
consisting of poloxamer or fatty acid polyoxyethylene ether.
20. An oral composition according to claim 1 that is substantially
free of added water.
21. An oral care composition according to claim 1, where the
composition is shelf stable for at least 6 months.
22. An oral care composition according to claim 1, where the
composition is shelf stable for at least 1 year.
23. An oral care composition according to claim 1, having an MIC of
less than 0.0025 mg/mL against Streptococcus mutans ATCC 25175,
Actinobacillus viscosus ATCC 15987, and/or Bacteriodes fragilis
ATCC 25285.
24. An oral care composition according to claim 1, having an MIC of
less than 0.00125 mg/mL against Streptococcus mutans ATCC 25175,
Actinobacillus viscosus ATCC 15987, and/or Bacteriodes fragilis
ATCC 25285.
25. An oral care composition according to claim 1, having an MBC of
less than 0.005 mg/mL against Streptococcus mutans ATCC 25175,
Actinobacillus viscosus ATCC 15987, and/or Bacteriodes fragilis
ATCC 25285.
26. An oral care composition according to claim 1, having an MBC of
less than 0.0025 mg/mL against Streptococcus mutans ATCC 25175,
Actinobacillus viscosus ATCC 15987, and/or Bacteriodes fragilis
ATCC 25285.
27. An oral composition according to claim 18 or 19, made according
to the process of: a) dispersing and swelling polyvinylpyrrolidone
in propylene glycol to obtain a first gel; b) dissolving the
poloxamer in heated propylene glycol to obtain a first solution; c)
adding the cationic biocide and any optionally included adjuvants
to the first solution and thoroughly mixing to form a second
solution; d) adding a first part of the fumed silica to the second
solution and homogenizing to obtain a second gel; e) mixing the
first gel and the second gel to obtain a first paste; f) adding a
second part of the fumed silica to the first paste and mixing to
obtain a second paste; g) dispersing a micronized peroxide source
powder evenly into the second paste to obtain an oral composition.
Description
BACKGROUND OF THE INVENTION
[0001] Biofilm is a collection of micro colonies with water
channels in between and an assortment of cells and extra cellular
glycoproteins, polysaccharides and proteins, nucleic acids, or
combinations of these macromolecules, and which protects the
inhabiting organisms from antiseptics, antibiotics, and host
cells.
[0002] In the oral environment, biofilms form when bacteria adhere
to surfaces in the oral cavity and begin to excrete a slimy,
glue-like substance that can adhere to all kinds of substrates
found in the oral environment, including biological tissues
(gingival tissues and oral mucosa tissues), enamel. dentin,
cementum, restoratives, metals, alloys, composites, plastics,
porcelains, medical implant materials and devices of prosthodontics
and orthodontics.
[0003] Biofilms in the oral environment contain communities of
disease-causing bacteria and their uncontrolled accumulation has
been associated with oral diseases, caries and periodontal diseases
(both gingivitis and periodontitis). An established oral biofilm
can be very difficult to disrupt, whether by mechanical or chemical
means.
[0004] The biofilm matrix may provide protection to biofilm-forming
bacteria from biocides. It has been well documented that
antimicrobials have difficulty penetrating the biofilm's surface
layer and because of that, they are less effective on bacteria in
an established biofilm, as compared to planktonic bacteria. It has
been estimated, for example, that bacteria within biofilms are
upwards of 1,000-fold more resistant to conventional antibiotics
(Rasmussen et al., Int. J. Med. Microbiol., 2006, 296: 149). As a
result, antimicrobial agents (such as antibiotics or antiseptics)
are generally not very effective in killing or inhibiting the
microorganisms that are deeply embedded within the biofilm. For
similar reasons, herbal extracts and essential oils also have very
low efficacy against biofilms.
[0005] In other contexts, strong antimicrobials have been used to
kill bacteria in a biofilm, such as Bisguanide, halogenated
diphenyl ether (e.g. triclosan); halogenated quaternary ammonium
compounds (e.g., hexadecylpyridinium chloride, benzalkonium
chloride, tetradecylpyridinium chloride,
N-tetradecyl-4-ethylpyridinium chloride); halogen compounds (e.g.,
elemental halogens, halogen oxides (e.g., NaOCl, HOCl, HOBr,
ClO.sub.2); interhalides (e.g., iodine monochloride, iodine
dichloride, iodine trichloride, iodine tetrachloride, bromine
chloride, iodine monobromide, or iodine dibromide); polyhalides,
hypochlorite salts, hypochlorous acid, and hypobromite salts.
Generally, these materials are effective in preventing the unwanted
growth of microorganisms. But, most of these compounds are not
suitable to be used in oral cavity due to the toxicities and
irritations to human body and oral tissues. Bisguanide antiseptics
have a bitter taste and stain tooth surfaces, making it unpleasant
to users. Triclosan is a potential mutagen, may cause hormone
imbalances, and may harm the immune system. Trislocan may also
increase the calcium levels inside neurons and with this,
theoretically, affect mental development.
[0006] Therefore, a high efficacy biocide without unwanted side
effects is in need for dental care.
[0007] Peroxides are known to be useful for cleaning and whitening
teeth, as well as killing cariogenic bacteria. However, peroxide
compounds are highly reactive and can spontaneously decompose. Some
known dentifrice compositions that include peroxide may exhibit an
unacceptable level of peroxide decomposition and loss of efficacy
as a result of being stored prior to sale or use. Moreover,
peroxide is not compatible with many commonly used ingredients in
toothpaste. Consequently, it has been difficult to formulate a
stable peroxide containing toothpaste.
[0008] Therefore, there is an ongoing and unmet need for an
effective composition for oral care, which combines a high efficacy
biocide without unwanted side effects and peroxide for effective
biofilm removal through the synergistic effect of a cationic
biocide and peroxide. The embodiments of the present invention aim
to meet these needs.
BRIEF SUMMARY OF THE INVENTION
[0009] The present invention provides a composition, which
comprises a stabilizing matrix, a peroxide source, and a cationic
biocide for inhibiting, reducing, and/or disrupting oral
biofilm.
[0010] The composition of invention provides an oral care
composition comprising (i) stabilizing matrix, (ii) a cationic
biocide, and (iii) a peroxide source.
[0011] The present invention also provides a composition according
to the above, having a stabilizing matrix that helps keep peroxide
and cationic biocide stable in a single-phase paste, which is
capable for long-term storage and is suitable for everyday consumer
use.
[0012] The present invention also provides a composition according
to any of the above, where the stabilizing matrix of the
composition maintains the efficacy of active ingredient, cationic
biocide, and at the same time to stabilizes the peroxide source in
the composition.
[0013] The present invention also provides a composition according
to any of the above, where the stabilizing matrix comprises of a
carrying agent, a thickening system and some compatible
adjuvants.
[0014] The present invention also provides a composition according
to any of the above, where the carrying agent of the matrix
comprises a polyhydric alcohol. In some embodiments, the polyhydric
alcohol may be propylene glycol.
[0015] The present invention also provides a composition according
to any of the above, where the propylene glycol is present in
amounts ranging from 75% to 85%, based on the matrix weight of the
composition.
[0016] The present invention also provides a composition according
to any of the above, where the stabilizing matrix comprises a
thickening system. In some embodiments, the thickening system of
the stabilizing matrix comprises polyvinylpyrrolidone and silicone
dioxide.
[0017] The present invention also provides a composition according
to any of the above, where polyvinvlpyrrolidone may be present in
amounts ranging from 2% to 6%, based on the matrix weight of the
composition.
[0018] The present invention also provides a composition according
to any of the above, where the thickening system of the stabilizing
matrix comprises a silicone dioxide. In some embodiment, the
silicone dioxide may be fumed silicone dioxide. In some
embodiments, the fumed silicone dioxide may be hydrophilic fumed
silicone dioxide.
[0019] The present invention also provides a composition according
to any of the above, where hydrophilic fumed silica may be present
in amounts ranging from 6% to 11%, based on the matrix weight of
the composition. In some embodiments, the hydrophilic fumed
silicone dioxide may be pharmaceutical grade.
[0020] The present invention also provides a composition according
to any of the above, where the compositions of the invention
optionally comprise an anti-caries agent. In some embodiments, the
invention may optionally include an effective amount of fluoride,
or a fluoride ion source. In certain embodiments, a fluoride ion
may be present in amounts ranging from 0.05% to 0.15%, based on the
weight of the composition.
[0021] The present invention also provides a composition according
to any of the above, where the stabilizing matrix of the
composition of present invention optionally comprises adjuvants
that are compatible with each other and compatible with the
cationic biocide and peroxide source in the system. In some
embodiments, adjuvants may include one or more foaming agents, one
or more flavorings, one or more coloring agents, one or more
chelating agents, one or more antioxidants, and the like.
[0022] The present invention also provides a composition according
to any of the above, where the peroxide source of the composition
may be selected from hydrogen peroxide, carbamide peroxide, calcium
peroxide, percarbonates, perborates, and cross-linked
polyvinylpyrrolidone complexed with hydrogen peroxide. In some
embodiments, the peroxide source is present in amounts ranging from
0.1% to 2.0%, optionally from 0.1% to 1.0%, optionally from 0.8% to
1.2%, based on calculated hydrogen peroxide weight of the
composition.
[0023] The present invention also provides a composition according
to any of the above, where the cationic biocide of the composition
is selected from group consisting of dual chain quaternary ammonium
biocide and a single chain quaternary ammonium biocide. In some
such embodiments, the cationic biocide may be PODA: Proline,
5-oxo-, ion(1-), N-decyl-N,N-dimethyl-1-decanaminium (1:1). In some
such embodiments, the cationic biocide may be Hexadecylpyridinium
chloride. In some embodiments, the cationic biocide may be present
in amounts ranging from 0.05% to 1.0%, optionally from 0.05% to
0.2%, optionally from 0.05% to 0.1%, based on the weight of the
composition.
[0024] The present invention also provides a composition, according
to any of the above, that provides a single phase oral care
composition that not only inhibits, reduces, and/or disrupts the
biofilm of oral cavities, but it also is stable for long-term
storage and is suitable for everyday consumer use.
[0025] By applying the composition to oral cavity in inhibition,
reduction, and disruption biofilm, the compositions of the present
invention can promote or improve oral health and/or systemic
health, including cardiovascular health. e.g., by reducing
potentials for systemic effects of inflammation from periodontal
disease
[0026] The present invention also provides a composition according
to any of the above, comprising (i) about 0.05% to about 0.2% of a
cationic biocide selected from the group consisting of a dual chain
quaternary ammonium biocide and a single chain quaternary ammonium
biocide, (ii) about 0.1% to about 2.0% of a compatible peroxide
source, and (iii) about 85% to about 99% of a stabilizing matrix,
where the percentages are based on the weight of the composition
and the percent of the peroxide source is calculated as a weight
percent equivalent as if the peroxide source were hydrogen
peroxide.
[0027] The present invention also provides a composition according
to any of the above, where the stabilizing matrix comprises a
carrier, a thickening system, and optionally further includes one
or more compatible adjuvants.
[0028] The present invention also provides a composition according
to any of the above, where the carrier is polyhydric alcohol. In
some embodiments, the polyhydric alcohol is propylene glycol and is
present in amounts of about 40% to about 90%, where the percentages
are based on the weight of the composition. In some embodiments,
the composition may have about 75% to about 85% propylene
glycol.
[0029] The present invention also provides a composition according
to any of the above, where the thickening system comprises
polyvinyl pyrrolidone. In some embodiments, the composition may
comprise about 2% to about 6% polyvinyl pyrrolidone, where the
percentages are based on the weight of the composition.
[0030] The present invention also provides a composition according
to any of the above, where the thickening system comprises fumed
silica. In some such embodiments, the fumed silica is hydrophilic
fumed silica and may be present in amounts of about 5% to about
11%, where the percentages are based on the weight of the
composition.
[0031] The present invention also provides a composition according
to any of the above, where the peroxide source is carbamide
peroxide.
[0032] The present invention also provides a composition according
to any of the above, where the cationic biocide is proline, 5-oxo-,
ion(1-), N-decyl-N,N-dimethyl-1-decanaminium (PODA).
[0033] The present invention also provides a composition according
to any of the above, where the cationic biocide is
hexadecylpyridinium chloride.
[0034] The present invention also provides a composition according
to any of the above, where the cationic biocide is proline, 5-oxo-,
ion(1-), N-decyl-N,N-dimethyl-1-decanaminium, the peroxide source
is carbamide peroxide, and the thickening system comprises
propylene glycol, polyvinylpyrrolidone, and hydrophilic fumed
SiO.sub.2.
[0035] The present invention also provides a composition according
to any of the above, where the cationic biocide is
hexadecylpyridinium chloride, the peroxide source is carbamide
peroxide, and the thickening system comprises propylene glycol,
polyvinylpyrrolidone, and hydrophilic fumed SiO.sub.2.
[0036] The present invention also provides a composition according
to any of the above, where the thickening system comprises a
compatible foaming agent selected from the group consisting of
poloxamer or fatty acid polyoxyethylene ether. In some such
embodiments, the compatible foaming agent may be poloxamer 188. In
some such embodiments, the compatible foaming agent may be fatty
alcohol polyoxyethylene ether 9.
[0037] The present invention also provides a composition according
to any of the above, where the composition is substantially free of
added water.
[0038] The present invention also provides a composition according
to any of the above, where the composition is shelf stable for at
least 6 months. In some such embodiments, the composition may also
be shelf stable for at least 1 year.
[0039] The present invention also provides a composition according
to any of the above, having an MIC of less than 0.0025 mg/mL
against Streptococcus mutans ATCC 25175, Actinobacillus viscosus
ATCC 15987, and/or Bacteriodes fragilis ATCC 25285.
[0040] The present invention also provides a composition according
to any of the above, having an MIC of less than 0.00125 mg/mL
against Streptococcus mutans ATCC 25175, Actinobacillus viscosus
ATCC 15987, and/or Bacteriodes fragilis ATCC 25285.
[0041] The present invention also provides a composition according
to any of the above, having an MBC of less than 0.005 mg/mL against
Streptococcus mutans ATCC 25175, Actinobacillus viscosus ATCC
15987, and/or Bacteriodes fragilis ATCC 25285.
[0042] The present invention also provides a composition according
to any of the above, having an MBC of less than 0.0025 mg/mL
against Streptococcus mutans ATCC 25175, Actinobacillus viscosus
ATCC 15987, and/or Bacteriodes fragilis ATCC 25285.
[0043] The present invention also provides a composition according
to any of the above, where the composition may be made according to
the process of: Dispersing and swelling polyvinylpyrrolidone in
propylene glycol to obtain a first gel. Dissolving the poloxamer in
heated propylene glycol to obtain a first solution. Adding the
cationic biocide and any optionally included adjuvants to the first
solution and thoroughly mixing to form a second solution. Adding a
first part of the fumed silica to the second solution and
homogenizing to obtain a second gel. Mixing the first gel and the
second gel to obtain a first paste. Adding a second part of the
fumed silica to the first paste and mixing to obtain a second
paste. Dispersing a micronized peroxide source powder evenly into
the second paste to obtain an oral composition.
DETAILED DESCRIPTION OF THE INVENTION
[0044] It should be understood that the detailed description and
specific examples, while indicating the preferred embodiment of the
invention, are intended for purposes of illustration only and are
not intended to limit the scope of the invention.
[0045] Unless otherwise indicated, the terms "%" or "percent" when
used in connection with an ingredient of the oral compositions of
the invention are intended to refer to the percent by weight of the
indicated ingredient in the composition.
[0046] The term "biofilm" refers to the diverse microbial community
(predominantly bacteria) found on the tooth surface, embedded in a
matrix of polymers of bacterial and salivary origin. Biofilm may be
used synonymously with dental plaque in the description of the
invention.
[0047] The present invention provides an oral care composition. The
composition may be administered to the substrate of enamel, dentin,
cementum, restorative metals, alloys, composites, plastics,
porcelains, medical implant materials and devices of prosthodontics
and orthodontics, to remove or disrupt oral biofilm or to reduce or
inhibit the formation of oral biofilm. The composition may also be
administered to an oral cavity to prevent or treat a condition
caused by oral biofilm formation in the oral cavity, wherein the
condition is selected from dental plaque, tooth decay, periodontal
disease, gingivitis or halitosis.
[0048] The present invention provides an oral care composition
having a cationic biocide, a peroxide source, and a stabilizing
matrix. Without intending to be bound by any particular theory, it
is believed that the cationic biocide and the peroxide source work
synergistically, to provide an enhanced activity against oral
biofilms and/or the bacteria within them. The stabilizing matrix
provides a system for keeping the cationic biocide and the peroxide
source shelf stable.
[0049] In accordance with the invention, the oral composition
contains a cationic biocide. A suitable cationic biocide may be
selected from a dual chain quaternary ammonium biocide and a single
chain quaternary ammonium biocide. In some such embodiments,
suitable dual chain quaternary ammonium biocides may include, for
example, N, N-Didecyl-N-methyl-poly(oxyethyl) ammonium propionate,
N,N-Didecyl-N,N-dimethylammonium carbonate,
N,N-di-n-decyl-N,N-dimethyl-ammonium N-acetylatedal alanine
carboxylate, Proline, 5-oxo-, ion(1-),
N-decyl-N,N-dimethyl-1-decanaminium (1:1). (PODA), 1-Decanaminium,
N-decyl-N, N-dimethyl-, salt with N-acetylalanine (1:1), Didoctyl
Dimethyl Ammonium Chloride, Didoctyl Dimethyl Ammonium bromide,
Ethylene-Di(Octadecyl Dimethyl Ammonium Chloride), Dioctadecyl
decamethylethylene diammonium bromide, and Dioctadecyl
decamethylethylene diammonium chloride. In other embodiments,
suitable single chain cationic biocides may include, for example,
N-Cocoyl-L-Arginineethylester DL-Pyrrolidonecarboxylate,
Hexadecelpyridinium chloride, Benzyldodecyldimethyl ammonium
bromide, Benzyldodecyldimethyl ammonium chloride, Dodecyl trimethyl
ammonium chloride, Dodecyl Trimethyl ammonium bromide,
Tetradecylpyridinium chloride, N-tetradecyl-4-ethylpyridinium
chloride, Cetyltrimethyl ammonium chloride, and Cetyltrimethyl
ammonium bromide. Other suitable cationic biocides or combinations
of cationic biocides, however, may be used. The cationic biocide
(or combination of cationic biocides) is generally present in the
oral composition in amounts that range from about 0.05% to about
2.0%, optionally from 0.1% to 1.0%, from 0.05% to 0.2%, optionally
from 0.05% to 0.1%, or optionally about 0.05%, 0.1%, 0.15%, or
0.2%, based on the weight of the composition.
[0050] In accordance with the invention, the oral composition
contains a peroxide source. In some embodiments, the composition of
present invention can include any of a variety of peroxide sources
or hydrogen peroxide source, e.g., urea peroxide (carbamide
peroxide) or hydrogen peroxide polymer complexes such as hydrogen
peroxide-polyvinyl pyrrolidone polymer complexes (cross-linked
PVP/H.sub.2O.sub.2 complex); percarbonates, perborates, or a
peroxide salt, such as calcium peroxide, strontium peroxide, barium
peroxide, and the like. In certain embodiments, the peroxide source
may be carbamide peroxide. In other embodiments, the peroxide
source may be hydrogen peroxide. In some embodiments, a combination
of peroxide sources may be used. In general, the peroxide source is
present in the oral composition in amounts ranging from about 0.1%
to about 2.0%. However, smaller amounts and larger amounts may be
used, for example, the composition may optionally contain a
peroxide source in amounts from about 0.05% to about 3%.
Optionally, the peroxide source may be present in the oral
composition in amounts from 0.1% to 1.0%, optionally from 0.8% to
1.2%, further optionally about 0.1%, 0.25%, 0.5%, 0.75%, 1.0%,
1.5%, or 2.0%, based on the calculated weight percent as if the
peroxide source were hydrogen peroxide. Thus, to calculate the
weight percent of a peroxide source as used herein, one would
multiply the weight percent of the peroxide source by the ratio of
the molecular weight of hydrogen peroxide over the molecular weight
of the peroxide source. In the case of carbamide peroxide, for
example, which has a molecular weight of 94.07 g/mol, one would
multiply the weight percent of the carbamide peroxide by 34.0147
over 94.07 (or about 0.362). Thus, an oral composition of the
invention having 2.76% carbamide peroxide, would have the
equivalent of 1% hydrogen peroxide.
[0051] As noted, the oral composition of the invention contains a
stabilizing matrix. The stabilizing matrix serves to maintain the
stability of one or more of the active ingredients of cationic
biocide and/or the peroxide source in the composition. The
stabilizing matrix generally comprises the bulk of the composition
and, as such, may comprise about 80% to about 99% of the
composition, optionally from 85% to 97%, further optionally from
90% to 98%, or further optionally about 94%, 95%, 96%, 97%, 98%,
99%, based on the weight of the composition.
[0052] In certain embodiments, the oral composition may be stable
for at least 6 months. In other embodiments, the oral composition
may be stable for at least 1 year. A stable oral composition of the
invention will be substantially free visible of bubble formation
resulting from the degradation of the peroxide source at the end of
the specified period of time, when stored at room temperature. A
stable oral composition of the invention that contains 0.002%
brilliant blue (E133) will similarly be substantially free of
visible loss in color over the specified time when stored at room
temperature.
[0053] The stabilizing matrix comprises a carrier, a thickening
system, and may optionally include compatible adjuvants. The
carrier provides a medium, which may dissolve, suspend, or carry
the other components of the composition. For example, the carrier
can provide a medium for solubilization, suspension, and/or for
forming an equilibrium mixture. The carrier can also function to
deliver and/or dissolve the active ingredients of the invention on
an object. To this end, the carrier may contain any orally
compatible component or components that can facilitate these
functions.
[0054] Generally, the carrier makes up a large portion of the
composition of the invention and may be the balance of the
composition apart from the thickening agents, cationic biocide,
peroxide source, adjuvants, and the like. The carrier is generally
a polyhydric alcohol, such as propylene glycol. The polyhydric
alcohol is generally present in amounts ranging from about 40% to
about 90%, from 40% to 65%, further optionally from 50% to 85%,
further optionally from 60% to 87%, or further optionally from
about 75% to about 85%, based on the weight of the composition.
[0055] The stabilizing matrix contains a thickening system. In
general, thickening agents generally considered orally-acceptable
include carboxyvinyl polymers, carbomers (polymers of acrylic
acid-bonded allyl sucrose or pentaerythritol allyl ether),
carrageenan, cellulosic polymers such as hydroxyl ethyl cellulose,
carboxymethyl cellulose (CMC) and salts thereof (e.g., CMC sodium),
natural gums such as karaya, xanthan gum, and colloidal magnesium
aluminum silicate, and mixtures of the same.
[0056] However, due to the special characteristics of the
invention, most of the above-mentioned thickening agents are not
usable for composition of the current invention. Some would
decompose the peroxide source rendering the system unstable; some
would decrease the efficacy of cationic biocide due to their
anionic nature, and most of the cellulose-derived thickeners are
not soluble in the carrier of the composition. Some thickening
agents, such as carbomers, natural gums such as karaya, xanthan
gum, carrageenan, etc., may be soluble in propylene glycol, but are
not suitable because of their anionic nature.
[0057] Thickening agents suitable for the thickening system of the
oral composition include polyvinylpyrrolidone and/or fumed silicon
dioxide, such as hydrophilic fumed silicon dioxide. These
thickening agents enable the oral composition to be stable and also
thicken the composition so that it can be extruded by a user from a
container, such as a tube, so as to enable the composition to be
used as a toothpaste or gel, and so that it can be readily
manufactured.
[0058] In some embodiments, the polyvinylpyrrolidone may be present
in amounts ranging from about 1% to about 6.0%, based on the weight
of the composition, optionally from 2% to 5%, optionally from 2.5%
to 4%, optionally about 2%, 2.5%, 3%,4%, or 5%, based on the weight
of the composition.
[0059] In some embodiments, the fumed silicon dioxide is
hydrophilic fumed silicon dioxide. In some embodiments, the fumed
silicon dioxide may be present in amounts ranging from about 4% to
about 11%, optionally from 6% to 10%, optionally about 6%, 7%, 8%,
9%, or 10%, based on the weight of the composition.
[0060] Decomposition of the peroxide may be induced by the presence
of various ingredients and trace ions within the ingredients. As
such, impurities in any ingredients may impact the stability of
peroxide in the system, particularly the presence of metal ions.
The known tolerance level for un-stabilized peroxide in the
presence of Al (III), Sn(IIIV), Zn(II), Fe(III), Cu(II), and Cr(II)
metal ions is presented in Table 1.
TABLE-US-00001 TABLE 1 Peroxide Tolerance level to Metal Ions
Amount Oxygen lost % Metal added (24 hr, ion (ppm) 100 C.)* Al
(III) 10 2 Sn(IIIV) 10 2 Zn(II) 10 10 Fe(III) 10 15 Cu(II) 0.01 24
Cr(II) 0.1 96 *Hydrogen peroxide not stabilized.
[0061] Consequently, hydrophilic fumed silicone dioxide with a very
low level of metal ions is preferred. The same is true for the
other component ingredients of the invention. Inclusion of
chelating agents, such as glycine, citric acid, acetic acid,
ethylene diamine tetraacetic acid (EDTA),
[0062] The oral care composition typically is a single-phase
composition, for example a dentifrice; for example toothpaste. For
the purposes of maintaining the stability of the composition, the
composition preferably contains less than 3%, less than 2%, less
than 1% water as an added ingredient. Typically, the present
invention is free or essentially free of added water beyond that
which might be naturally present in the other components of the
composition. Optionally, the composition of the invention may be an
anhydrous or essentially anhydrous system.
[0063] As noted, the stabilizing matrix may optionally contain
adjuvants, which are compatible with each other and compatible with
cationic biocide and peroxide source. Typical categories of
adjuvants include a fluoride source, foaming agents, sweetening
agents, flavorings, coloring agents, chelating agents,
antioxidants, and the like.
[0064] However, many materials commonly used in oral care
composition , such as, tartar control agents e.g., phosphates and
polyphosphates (for example pyrophosphates); anti-calculus agents,
e.g., tetrasodium pyrophosphate (TSPP) and sodium tripolyphosphate
(STPP); natural calcium carbonate (NCC), precipitate calcium
carbonate (PCC), are not compatible with the system, due to their
incompatibility with the cationic biocide or the peroxide sources
utilized in the invention.
[0065] In certain embodiments, the compositions of the invention
optionally comprise a compatible anti-caries agent, such as an
effective amount of fluoride, or a fluoride ion source. A wide
variety of fluoride ion-yielding materials can be employed. Typical
fluoride ion sources used in toothpastes include, but are not
limited to, stannous fluoride, sodium fluoride, and sodium
monofluorophosphate. However, it was determined that sodium
monofluorophosphate is not compatible with the system of the
composition. Typically, in those embodiments containing a source of
fluoride ion, the choice of the fluoride source will be sodium
fluoride.
[0066] In those embodiments have a fluoride ion source as an
adjuvant, the fluoride ion is generally present in amounts ranging
from about 0.001% to 1.5% based on the weight of the composition,
further optionally from 0.1% to 0.15%, further optionally from
0.05% to 0.1%, based on the weight of the composition. The specific
weight of the fluoride salt or salts utilized to provide the
appropriate level of fluoride ion will vary based on the weight of
the counter ion in the salt.
[0067] As noted, one or more compatible foaming agents may
optionally be included as an adjuvant. Sodium lauryl sulfate (SLS)
and sodium laureth sulfate (SLES) are both widely used in oral care
products. (The other name for sodium lauryl sulfate is sodium
dodecyl sulfate (SDS); usually called K12 in the dental industry.)
The main use for SLS and SLES in toothpaste or oral care products
is as a foaming agent to create lather, which gives an impression
of cleaning power. However, SLS and SLES can irritate oral mucosa,
eyes, skin, and lungs, especially with long-term use. SLES may also
be contaminated with a substance called 1,4-dioxane, which is known
to cause cancer in laboratory animals. This contamination occurs
during the manufacturing process. Many health care products with
sulfates are tested on animals to measure the level of irritation
to people's skin, lungs, and eyes. For this reason, many oppose
using consumer products that contain SLS and SLES. For people with
an allergic constitution, sulfates may cause oral mucosal shedding
and other problems. With the concern of irritation and potential
adverse health effects, many people are going sulfate-free.
Moreover, SLS was determined to be incompatible with the system of
the invention.
[0068] In looking for a safe and compatible substitute foaming
agent, various compounds were evaluated in either water or
propylene glycol. The foaming agents tested included: Coconut oil
acid diethanolamine, Cocamidopropylbetaine, Fatty alcohol
polyoxyethylene ether, Sodium myristyl glutamate,
N-Cocoyl-L-glutamic acid monotriethanolamine (Amisoft CT-12S),
Sodium dodecyl sulfate, Lauryl glucoside, and Polyoxyethylene
ether. The results are displayed in Tables 2 and 3. It was
determined that fatty alcohol polyoxyethylene ether and poloxamer
are compatible with the system of the invention.
[0069] Poloxamers are nonionic tri-block copolymers composed of a
central hydrophobic chain of polyoxypropylene (polypropylene oxide)
flanked by two hydrophilic chains of polyoxyethylene, poly
(ethylene oxide). Poloxamers are commonly used in industrial
applications, cosmetics, and pharmaceuticals as emulsifier. As a
substitute foaming agent, poloxamer proved to be a safe and
efficient foaming agent that is also compatible with the system of
the invention.
[0070] One or more compatible foaming agents, such as fatty alcohol
polyoxyethylene ether or a poloxamer (such as Poloxamer 188 or
Poloxamer 407) or mixtures thereof may be present in amounts
ranging from about 0.5% to about 4%, from about 1.0% to about 3%,
or from about 2% to about 3% in various embodiments, based on the
weight of the composition.
[0071] The compositions of the invention may optionally comprise
one or more orally-acceptable antioxidants as an adjuvant. Any
antioxidant that is orally-acceptable and compatible with the
system of the invention, may be used e.g., butylated hydroxyanisole
(BHA), butylated hydroxytoluene (BHT), ascorbic acid, herbal
antioxidants, and mixtures thereof. In some embodiments, one or
more antioxidants may be present in amounts ranging from of 0.01%
to 0.03% based on the weight of the composition.
[0072] As noted, the compositions of the invention may optionally
comprise one or more flavoring agents as an adjuvant. Any flavoring
that is orally-acceptable and compatible with the system of the
invention, may be used. Experiment discovered that the commonly
used oil soluble peppermint is not compatible with the system.
However, water soluble peppermint is compatible with the system, as
are other common flavoring agents such as menthol. In some
embodiments, one or more flavoring agents may be present in amounts
ranging from 0.5% to 3.0%; or from 0.8% to 1.6%, optionally from to
0.6% to 0.8%, or optionally about 0.5%, 1.0%, 1.5%, 2.0%, or 2.5%,
based on the weight of the composition.
[0073] The compositions of the invention may optionally contain one
or more coloring agents as an adjuvant. Any coloring agent that is
orally-acceptable and compatible with the system of the invention.
In some embodiments, one or more coloring agents may be present in
amounts ranging from 0.001% to 0.1%, based on the weight of the
composition.
[0074] The compositions of the invention may also optionally
contain one or more compatible sweetening agents as an adjuvant.
Any sweetening agent that is orally-acceptable and compatible with
the system may be used. For example, sucralose and sodium
saccharin, and combinations thereof, are compatible with the
invention and may be present in amounts ranging from about 0.1% to
about 2.0%, depending on the desired flavor profile for the
composition.
[0075] The compositions of the invention may optionally contain one
or more chelating agents as an adjuvant, such as citric acid,
acetic acid, ethylene diamine tetraacetic acid, or a mixture of two
or more thereof. Chelating agents may be useful for binding to free
metal ions, thereby help to prevent decomposition of the peroxide
and to increase the stability and shelf life of the composition. In
some embodiments, one or more chelating agents are present in
amounts ranging from about 0.01% to about 0.1%, based on the weight
of the composition.
[0076] System Stability Evaluation
[0077] A wide variety of orally-used ingredients were evaluated for
their compatibility with a peroxide source, including:
Cocamidopropyl betaine (CAB 97), Fatty Alcohol Polyoxyethylene
Ether 9 (AEO 9), Sodium Myristyl Glutamate, N-Cocoyl-L-glutamic
acid monotri-ethanolamine (Amisoft: Amisoft CT-12S), Sodium Dodecyl
Sulfate, Lauryl glucoside, Acetylated di-starch phosphate, Guar
hydroxylpropyltrimonium chloride, Cationic pre-gelatinized starch,
Hydrated SiO2 ZD 115, Hydrated SiO2 ZD165, Laponite XLG (lithium
magnesium silicate, a synthetic clay), Carboxyvinyl polymers, Fatty
alcohol polyoxyethylene ether (Polyox WSR), Glycerin,
Polyvinylpyrrolidone, Carboxymethyl cellulose, Sodium carboxymethyl
cellulose, Sodium tripolyphosphate (STPP), Tetrasodium
pyrophosphate (TSPP), Sucralose, Fumed silica, Water soluble
peppermint (Fermenich, APL0504), 1-Hexadecylpyridinium Chloride,
Calcium carbonate, Calcium pyrophosphate, Sorbitol, Sodium
monofluorophosphate, Sodium pyrophosphate, Sodium fluoride,
Precipitate calcium carbonate, Sodium saccharin, Disodium EDTA,
Menthol, Oil soluble peppermint (Firmenich, F89P961), Poloxamer188,
and Poloxamer 407. The results are displayed in Tables 2 and 3.
[0078] A 0.002% solution of Brilliant Blue (E133) in propylene
glycol or DI water as a baseline indicator of possible hydrogen
peroxide activation was made. 20 mL of the propylene glycol color
solution of was placed in a clear glass jar as a negative control
for the propylene glycol group; 20 mL of the aqueous color solution
was placed in a clear glass jar as a negative control for the water
group. The remaining propylene glycol and DI water color solutions
had carbamide peroxide added, to make 2.76% (equivalent to 1%
H.sub.2O.sub.2) carbamide peroxide solutions. 20 mL of each
solution with carbamide was put in a clear glass jar as positive
controls separately.
[0079] Each test compound was put into two clear glass jars with 20
mL of the above polypropylene glycol/Brilliant Blue/carbamide
peroxide and the DI water/Brilliant Blue/carbamide solutions. Any
color dissipation over time (lightening of the color) meant that
carbamide peroxide in the solution was activated and decomposition
had occurred. An oxidation process occurs when the peroxide is
activated thereby breaking the bonds of chromospheres, which leads
to color dissipation or clearing. Compounds that resulted in color
clearing were determined to have poor stabilizing effect and deemed
incompatible with the system.
[0080] The results of the evaluation are displayed in Table 2 and
Table 3. The negative control, positive control, and test jars were
sealed, kept at room temperature and kept away from light. After 60
days, if the color was entirely dissipated, the compound was deemed
to be incompatible with peroxide or the system. If there was no
color dissipation or only slight dissipation, the compound was
deemed compatible with the peroxide source and the system. If there
was obvious color dissipation, the compound was deemed still
potentially compatible with the system if suitably stabilized.
[0081] Color fading grades: no color dissipation (++++); slightly
dissipation (+++); obvious dissipation (++); totally dissipated
(+).
TABLE-US-00002 TABLE 2 Stability Test in Aqueous System (2.76%
Carbamide Peroxide in Water (equals to 1% H.sub.2O.sub.2) Compound
Amount Color Compound Amount Color Positive control + Negative
control ++++ Guar 1% + Sodium Dodecyl 1% + hydroxypropyl- Sulfate
trimonium chloride Cationic 1% + Cocamidopropyl 2% ++++
pre-gelatinized betaine starch Polyquaternium-4 1% + Fatty Alcohol
2% +++ Polyoxyethylene Ether 9 Hydrated SiO.sub.2 10% + Natural
calcium 15% + carbonate Glycerin 20% + Sodium acid 1% ++
pyrophosphate Carboxymethyl 1% + Sucrose fatty 1% + cellulose acid
ester Sodium 1% + Sorbitol 60% + carboxymethyl cellulose Laponite
XLG 2% + Sodium 0.1% + monofluoro- phosphate Amisoft CT-12S 1% +
Calcium 10% + pyrophosphate Lauryl glucoside 2% + Sodium fluoride
0.1% ++ Sodium 5% Precipitate calcium 15% + tripolyphosphate
carbonate Tetrasodium 5% + Sodium saccharin 0.5% ++ pyrophosphate
Sucralose 0.5% ++ Disodium EDTA 0.1% +++ Fumed silica 5% +++
Menthol 0.1% +++ Acetylated di-starch 1% + Poloxamer 188 2% +++
phosphate Water soluble 1% +++ Premium 1% + Peppermint peppermint
(Fermenich, (Firmenich, APL 0504) F89P961) Hexadecyl- 0.1% +
Poloxamer 407 2% ++ pyridinium Chloride PODA 0.1% + Polyvinyl- 3%
++ pyrrolidone PVP cross-linked Chlorhexydine 0.1% + H.sub.2O.sub.2
++++ Laponite XLG: lithium magnesium silicate, synthetic clay PODA:
Proline, 5-oxo-, ion(1-), N-decyl-N,N-dimethyl-l-decanaminium
(1:1). Amisoft CT-12S: N-Cocoyl -L-glutamic acid
monotriethanolamine
TABLE-US-00003 TABLE 3 Stability Test in Propylene Glycol 2.76%
Carbamide peroxide in propylene glycol (equals to 1%
H.sub.2O.sub.2) Compound Amount Color Compound Amount Color
Positive control +++ Negative control ++++ Guar 1% + Sodium Dodecyl
1% + hydroxypropyl- Sulfate trimonium chloride Cationic pre- 1% +
Cocamidopropyl 2% ++++ gelatinized starch betaine Polyquaternium-4
1% + Fatty alcohol 2% +++ polyoxyethylene ether Hydrated SiO.sub.2
10% + Natural calcium 15% + ZD115 carbonate Glycerin 20% ++ Sodium
acid 1% ++ pyrophosphate Carboxymethyl 2% + Sucrose fatty 1% +
cellulose acid ester Sodium 1% + Sorbitol 60% + carboxymethyl
cellulose Laponite XLG 2% + Sodium 0.1% + monofluoro- phosphate
Amisoft CT-125 1% + Calcium 10% + pyrophosphate Lauryl glucoside 2%
+ Sodium fluoride 0.1% +++ Sodium 5% + Precipitate calcium 15% +
tripolyphosphate carbonate Tetrasodium 5% + Sodium saccharin 0.5%
+++ pyrophosphate Sucralose 0.5% +++ Disodium EDTA 0.1% +++ Fumed
silica 5% +++ Menthol 0.1% +++ Acetylated 1% + Poloxamer 188 2% ++
di-starch phosphate Water soluble 1% +++ Premium 1% + peppermint
peppermint (Firmenich, (Firmenich, (APL0504) F89P961) Hexadecyl-
0.1% ++ Poloxamer 407 2% ++ pyridinium Chloride PODA 0.1% ++
Polyvinyl- 3% +++ pyrrolidone PVP Cross-linked Chlorhexydine 0.1%
++ H.sub.2O.sub.2 3% ++++ Laponite XLG: lithium magnesium silicate,
synthetic clay PODA: Proline, 5-oxo-, ion(1-),
N-decyl-N,N-dimethyl-l-decanaminium (1:1). Amisoft CT-12S: N-Cocoyl
-L-glutamic acid monotriethanolamine
[0082] Results of testing demonstrated that many commonly used
ingredients for dentifrice would activate the peroxide and make the
system unstable, such as: Hydrated SiO.sub.2, Sodium
tripolyphosphate (STPP), Tetrasodium pyrophosphate (TSPP),
Precipitate calcium carbonate, Natural calcium carbonate, Calcium
pyrophosphate, Sorbitol, Sodium Dodecyl Sulfate, Colloidal silica,
Sodium monofluorophosphate, Sorbitol, Glycerin, Sodium
carboxymethyl cellulose, Carboxymethyl cellulose, etc. Any
peroxide-containing formulation would not be stable with any of the
above ingredients in the system.
[0083] System Stability Evaluation:
[0084] To assess the stability of some prior art
peroxide-containing dentifrices, the following experiments were
performed:
[0085] U.S. Pat. No. 9,999,585 describes an oral care composition
comprising (i) a whitening complex comprising cross-linked
polyvinylpyrrolidone complexed with hydrogen peroxide, and (ii) a
hydrogen peroxide stabilizing agent comprising clay comprising a
sodium lithium magnesium silicate.
[0086] U.S. Pat. No. 10,052,270 describes an oral care composition
comprising (i) a peroxide whitening agent comprising a whitening
complex of cross-linked polyvinylpyrrolidone complexed with
hydrogen peroxide, (ii) sodium acid pyrophosphate
(Na.sub.2H.sub.2P.sub.2O.sub.7) in an amount of from 0.1 wt % to 3
wt % based on the weight of the composition, and (iii) less than 3
wt. % water based on the weight of the composition; and further
comprising at least one humectant; wherein the at least one
humectant comprises propylene glycol and glycerin, and wherein the
composition comprises propylene glycol and glycerin in an amount of
from 25 wt. % to 60 wt. % based on the weight of the composition;
and further comprising 1 to 2 wt. % tetrasodium pyrophosphate as an
tartar control agent.
[0087] Two compositions were prepared according to U.S. Pat. No.
9,999,585 (formulations 585a and 585b) and two compositions were
prepared according to U.S. Pat. No. 10,052,270 (formulations 270a
and 270b), as set out in Table 4 below. The stability of
formulations using cross-linked PVP/H.sub.2O.sub.2 complex (585a
and 270a) or carbamide peroxide (585b and 270b) as peroxide sources
were evaluated in the compositions.
TABLE-US-00004 TABLE 4 Prior Art Compositions Tested for Stability
585a 270a 585b 270b Fumed silica -- 1.5 -- 1.5 85% syrupy
phosphoric acid 0.2 0.2 0.2 0.2 PEG 600 3 10 3 10 Pluracare L1220F
7.5 10 7.5 10 Glycerin 23.61 5 23.61 5 Propylene glycol 28 25 28 25
Sodium lithium magnesium silicate 2 -- 2 -- Cross-linked PVP 2 2 2
2 Cross-linked PVP/H.sub.2O.sub.2complex 11 5.5 0.0 0.0 Carbamide
peroxide 0.0 0.0 3.0 3.0 Sodium saccharin 0.6 0.6 0.6 0.6 Sodium
monofluorophosphate 0.76 0.76 0.76 0.76 Tetrasodium pyrophosphate
(TSPP) 2 2 2 2 Butylated hydroxytolune (BHT) 0.03 0.03 0.03 0.03
Sodium lauryl sulfate (SLS) 2 2 2 2 Calcium pyrophosphate 15 35.11
15 35.11 Sodium acid pyrophosphate -- 1.0 -- 1.0 Brilliant Blue
(E133) 0.002 0.002 0.002 0.002
[0088] Test samples 585a, 585b and test samples 272a, 272 b were
placed in sealed clear glass jars at room temperature and kept away
from light. After 24 hours, the color of formulations 585a, 585b,
and 272a had disappeared. The paste became colorless and many
bubbles appeared in the paste. The color of formulation 272b had
minor dissipation with a few bubbles. After 3 days, the color of
formulation 272b disappeared as well. The paste became colorless
and many bubbles appeared.
[0089] With sodium acid pyrophosphate
(Na.sub.2H.sub.2P.sub.2O.sub.7) as peroxide stabilizer
(formulations 270a and 279b), the composition was not stable with
either Cross-linked PVP/H.sub.2O.sub.2 complex or carbamide
peroxide as a peroxide source.
[0090] With sodium lithium magnesium silicate (Laponite XLG) as
peroxide stabilizer (formulations 585a and 585b), the system was
not stable with either Cross-linked PVP/H.sub.2O.sub.2 complex or
carbamide peroxide as a peroxide source.
[0091] A composition according to U.S. Pat. No. 9,999,585 (claim
27) was also prepared for the stability evaluation.
TABLE-US-00005 TABLE 5 Prior Art Formulation with Sodium Lithium
Magnesium Silicate Composition W/W Sodium lithium magnesium
silicate (Laponite XLG) 2 Cross-linked polyvinylpyrrolidone 2
Glycerin 30 Propylene glycol 30.5 Pluracare L1220F 7.5 Polyethylene
glycol 600 3 Cross-linked PVP/H.sub.2O.sub.2 complex 10 Calcium
pyrophosphate 15 Brilliant Blue (E133) 0.002
[0092] The above composition was prepared and placed in sealed
clear glass jars at room temperature, and kept away from light.
After 3 days, the blue paste became colorless and many bubbles
appeared in the paste.
[0093] With sodium lithium magnesium silicate (Laponite XLG) as a
peroxide stabilizer, the system was not stable with Cross-linked
PVP/H.sub.2O.sub.2 complex as a peroxide source.
EXAMPLE 1
Example Formulations
[0094] Several compositions of the invention are illustrated in the
following non-limiting examples (Table 6). Each example composition
comprises the following ingredients, each being based on the weight
of the composition.
TABLE-US-00006 TABLE 6 Formulations Ingredient 1 2 3 4 5 6 7
Proline, 5-oxo-, ion(1-), N- 0.10 0 0.05 -- 0.10 -- 0.20
decyl-N,N-dimethyl-l- decanaminium Polyvinylpyrrolidone 2.00 2.00
5.00 2.50 2.50 4.00 2.00 Fumed SiO.sub.2 9.00 9.00 5.00 8.00 10.00
7.00 9.00 Carbamide peroxide 2.86 2.86 5.72 5.72 0.29 1.43 2.86
Hexadecylpyridinium -- 0.10 -- 0.05 -- 0.20 -- Chloride Menthol
0.10 0.10 0.05 0.05 -- 0.10 0.01 Sodium fluoride 0.10 0.05 0.10 --
-- -- -- Water soluble Peppermint 1.00 1.00 1.50 1.00 -- 1.00 2.00
Sucralose 0.60 -- 0.50 -- -- -- 0.70 Saccharin sodium -- 0.60 --
0.50 -- 0.70 -- Paloxamer 188 3.00 -- 3.00 -- -- -- -- Fatty
Alcohol -- 3.00 -- 3.00 -- 3.00 3.00 Polyoxyethylene Ether 9
Brilliant Blue (E133) 0.002 0.002 0.002 0.002 0.002 0.002 --
Propylene glycol qs 100 qs 100 qs 100 qs 100 qs 100 qs 100 qs
100
[0095] It is understood that when formulations are described, they
may be described in terms of their ingredients, as is common in the
art, notwithstanding that these ingredients may react with one
another in the actual formulation as it is made, stored and used,
and such products are intended to be covered by the formulations
described.
EXAMPLE 2
Process for Mixing the Composition
[0096] The procedures for preparation of the composition:
[0097] a. Polyvinylpyrrolidone is dispersed in propylene glycol to
let the polyvinylpyrrolidone totally swell, to obtain Gel A;
[0098] b. Poloxamer is dissolved in heated propylene glycol
(45.degree. C.) to obtain Solution B;
[0099] c. The cationic biocide and adjuvants are added to solution
B, thoroughly mixed at room temperature to obtain Solution C;
[0100] d. The fumed silica is divided into three parts. One third
of the fumed silica is added to solution C, homogenized and then a
second part of fumed silica is added, then homogenized, to obtain
Gel B;
[0101] e. Gel A and Gel B are thoroughly mixed, to obtain a
homogeneous paste A;
[0102] f. The last part of the fumed silica is added to the paste A
and thoroughly homogenized to obtain paste B.
[0103] g. The micronized peroxide source powder is then dispersed
evenly to the above paste B, to obtain the final product.
[0104] h. Discharge batch.
[0105] All the mixing occurs between about 24.degree. C. to
29.degree. C., preferably room temperature.
EXAMPLE 3
Stability Testing
[0106] Several toothpastes of varying compositions were prepared
and tested for stability using indicators outlined previously.
[0107] Sample 1 (Example 1, formulation 1), Sample 2 (Example 1,
formulation 3), Sample 3 (Example 1, formulation 5), and Sample 4
((Example 1, formulation 2) were prepared according to the
procedures of Example 2.
[0108] Sample 1, Sample 2, Sample 3 and Sample 4 were prepared and
put in sealed clear glass jars at room temperature and kept away
from light. Color dissipation and bubble generation were used as
indicators of the hydrogen peroxide decomposition. Any lightening
of color or bubble generation meant carbamide peroxide in the paste
was activated and decomposition had occurred indicating
instability.
[0109] After 6 months, no color change or bubble generation was
observed, thereby confirming the stability of the composition of
the invention.
[0110] The Sample 1, Sample 2 and Sample 3 were used for tests in
Example 4, Example 5 and Example 6.
EXAMPLE 4
MIC and MBC of the Composition Against S. mutans and A.
viscosus
[0111] Agar Dilution method recommended by National Committee for
Clinical Laboratory Standards (NCCLs) were used to determine the
minimum inhibitory concentration (MIC) and minimum bactericidal
concentration (MBC) of Streptococcus mutans and Actinobacillus
viscosus, the main bacteria in oral biofilm and the most important
pathogenic bacteria for dental caries and periodontal diseases.
[0112] Test sample and the bacteria strains:
[0113] 1. Test sample: Example 1, formulation 5 (stored 6 month
before test)
[0114] 2. Streptococcus mutans (ATCC 25175)
[0115] 3. Actinobacillus viscosus (ATCC 15987)
[0116] 4. Bacteriodes fragilis (ATCC 25285) (for quality
control)
[0117] Procedures: [0118] 1. The test sample was vortex mixed with
DI water to make serial diluted slurry solutions at: 1/10, 1/20,
1/40, 1/80, 1/160, and 1/320 concentrations. [0119] 2. 50 mL of
each of each serially diluted slurry was centrifuged for 15 min. at
15000 rpm. at room temperature. The supernatant was kept for use.
[0120] 3. 1 mL of each of the above supernatant was mixed with 9 mL
BHI sterilized agar, and prepared in agar plates. The concentration
in the agar plates was 1/100, 1/200, 1/400. 1/800, 1/1600, and
1/3200 respectively. [0121] 4. Resuscitation and purification of
the testing strains was conducted according conventional culture
method for anaerobic bacteria. Cultured for 48 hours, medium: BHI-S
(XOID, England); anaerobic tank: DY-II (YiWu) with 80% N2+10%
CO2+10% H2. The pure cultures were inoculated into BHI medium and
cultured under the same conditions for 48 hours; with the bacterial
concentration of 48-hour cultures adjusted to 0.5 McFarland
(1.5.times.10.sup.8 cells/mL). [0122] 5. MIC and MBC determination:
48 hour cultures (1.5.times.10.sup.8 cells/mL) were inoculated with
a bacterial multipoint plater (SAKUMA, Japan) to the agar plates
with different sample concentrations; cultured 48 hrs. in an
anaerobic tank with 80% N2+10% CO2+10% H2 . The MIC and MBC values
were then recorded. [0123] 6. Results: The MIC and MBC of the test
sample are shown in Table 7.
TABLE-US-00007 [0123] TABLE 7 MIC and MBC for S. mutans and A.
viscosus Streptococcus Actinobacillus Bacteriodes fragilis mutans
viscosus (control strain) MIC 1/800 1/800 1/800 MBC 1/400 1/400
1/400
[0124] The MIC and MBC for Streptococcus mutans (ATCC 25175) was
1/800 and 1/400, respectively. Similarly, the MIC and MBC for
Actinobacillus viscosus (ATCC 15987) was also 1/800 and 1/400
respectively. For comparison, a 2016 publication determined that
amongst the dentifrices tested (Colgate.RTM. Total.RTM.,
Colgate.RTM. Cavity Protection.RTM., Crest.RTM. Pro-Health.RTM.,
and Crest.RTM. Pro-Health Clinical.RTM.)), Colgate.RTM. Total.RTM.,
containing 0.3% trislocan, had the lowest MBC against streptomyces
under anaerobic conditions, with an MBC of 3.1-5.2 mg/ml and an MIC
against total oral anaerobes of about 1.5 mg/mL. (Forbes et al.,
Simultaneous Assessment of Acidogenesis Mitigation and Specific
Bacterial Growth Inhibition by Dentifrices, PLoS One. 2016; 11(2):
e0149390). This represents an MIC and MBC that is three orders of
magnitude higher than the dentifrice of the present invention,
which demonstrated MBC and MIC values of around 0.0025 mg/mL and
0.00125 mg/mL, respectively. Without intending to be bound by any
particular theory, it is believed that there is a synergism between
the cationic biocide and the peroxide that enhances the
antibacterial activity in the formulations of the present
invention.
EXAMPLE 5
Existing Biofilm Disruption
[0125] Twenty (10 pairs) of freshly extracted first upper premolars
from orthodontic patients were used for the study. Right after
removal from the mouth, the teeth were rinsed with saline, and the
crown was stained with Ci plaque indicator (Ci Medical CO, Ltd.) to
disclose existing biofilms. The teeth were rinsed with saline and
photos were taken of the labial, distal, mesial and lingual
surfaces of each tooth. The stained area was then measured
according to the index classification to determine biofilm
index.
[0126] A 1.5 g sample of toothpaste (Example 1, composition 1,
sample stored for 6 month before test) was vortex mixed with 8.5 g
deionized water for 3 min to make a sample solution (solution S).
Deionized water was used for a comparative solution (solution C).
One tooth from a pair of stained teeth from the same patient was
randomly immersed in each solution (one tooth from the pair in
solution S; one tooth from the pair in solution C). The specimens
were void of any mechanical disturbance. There were 10 teeth in the
sample group and 10 teeth in the comparative group. The teeth in
solution S were designated as T1 to T10; the teeth in solution C
were designated as C1 to C10. The pair of teeth were removed from
solution S and solution C, respectively, rinsed with saline,
stained, and the biofilm index was recorded for the four sides of
each tooth at 10 min., 20 min., and 40 min. intervals.
[0127] Results:
[0128] Calculate the mean index value of labial, distal, mesial and
lingual surface index readings of each tooth. Use the mean index
value as the index of the tooth at each time interval.
TABLE-US-00008 TABLE 8 Biofilm Index Change after Toothpaste
Treatment Test pair 0 min. 10 min. 20 min. 30 min. 40 min. T 1 3.5
2.5 2.5 2.5 2.5 C 1 3.5 3.5 3.5 3.5 3.5 T 2 4 3.5 3.25 3.25 3.25 C
2 4 4 4 4 4 T 3 4.5 3.75 3.5 3.5 3.25 C 3 4.25 4.25 4.25 4.25 4.25
T 4 3.25 3 2.75 2.5 2.25 C 4 3.25 3.25 3.25 3.25 3.25 T 5 3.5 3.25
3.25 3.25 3 C 5 3.5 3.5 3.5 3.5 3.5 T 6 3.75 3.5 3.25 3.25 3.25 C 6
3.75 3.75 3.75 3.75 3.75 T 7 3.75 3.25 3.25 3.25 2.75 C 7 3.25 3.25
3.25 3.25 3.25 T 8 4 3 2.5 2.5 2.5 C 8 4 4 4 4 4 T 9 4 3.75 3.75
3.75 3.75 C 9 4 4 4 4 4 T 10 4.25 4.25 4.25 4.25 4.0 C 10 4.25 4.25
4.25 4.25 4.25 Biofilm index grading: 0 = no stain on the tooth
surface; 1 = scattered stain at gingival margin; 2 = stain covering
the gingival margin is less than 1 mm; 3 = stain covering the
gingival margin is over 1 mm but less than 1/3 of the tooth
surface; 4 = stain covering 1/3-2/3 of the tooth surface; 5 = stain
covering 2/3 of the tooth surface.
[0129] In the sample group, after 40 min. treatment, the biofilm
was reduced by 21%. There were no changes in the comparative group.
Conclusion: The sample toothpaste demonstrated a capacity to
reduce/disrupt existing biofilm on human teeth.
EXAMPLE 6
Artificial Biofilm Disruption
[0130] Twenty-four bovine permanent central incisors were cut to
obtain 24 labial enamel specimens approximately 10 mm.sup.2. The
enamel specimens were embedded in an auto-polymerizing methacrylate
resin in such a manner that only the enamel surfaces were exposed.
The specimens were embedded with the aid of a mold so as to
facilitate the positioning of the specimens in a V-White brushing
machine. The enamel surfaces were rubbed with 600 grit silicon
carbide sand paper under constant flow water. Surfaces were then
polished with a dental polishing paste. Specimens were then lightly
etched. This etching procedure consisted of a 60-second immersion
in 0.12N (1%) hydrochloric acid, followed by a 30-second immersion
in a super-saturated solution of sodium carbonate to expedite stain
accumulation and adherence. A final etch was performed with 1%
phytic acid for 60 seconds. The specimens were then rinsed and
ultrasonically cleaned in deionized water. After air-drying, the
specimens were treated in a staining/bacteria broth. The
staining/bacteria broth consisted of 2.7 g of finely ground instant
coffee, 2.7 g of finely-ground instant tea, and 2.0 g of
finely-ground gastric mucin dissolved into 800 ml of sterilized
trypticase soy broth. Twenty-six ml of a 24-hour Sarcocyst (Sarcina
lutea turtox) culture was also added to the staining broth.
[0131] The specimens were immersed in the staining/bacteria broth
in a staining container and the container was then placed in an
incubator (37.degree. C.) with the specimens remaining immersed in
the staining/bacteria broth. The staining/bacteria broth was
replaced twice daily, for seven consecutive days. With each broth
change, the specimens were rinsed with deionized water to remove
any loose deposits. After the seven-day staining period, a darkly
stained film was apparent on the enamel surfaces. The specimens
were removed from the staining container, rinsed well, allowed to
air dry for about ten minutes, and then refrigerated until use.
[0132] Each specimen was scanned with a 3 Shape Trios intraoral
scanner (Denmark) to determine the L* value. The specimens were
divided into two groups; one test group and one comparative group.
Each specimen was given a numerical number from 1-24 and evenly
divided into Sample group and Comparative group according to their
L* readings. Each group had 12 specimens and the Sample and
Comparative groups were balanced to include specimens with similar
L* values. The Sample group had teeth T1, T2, T3, T4, T5, T6, T7,
T9, T10, T12, T13, T14; and the Comparative group had teeth T8,
T11, T15, T16, T17, T18, T19, T20, T21, T22, T23, T24.
[0133] A computer color matching (CCM) system of the body color of
29 shade tabs from a VITAPAN 3D-Master shade guide was used to
match the specimen readings from the 3 Shape-Trio readings. The 29
shades of the VITA shade guide 3-D values are: 0M1, OM2, OM3, 1M1,
1M2, 2L1.5, 2L2.5, 2M1, 2M2, 2M3, 2R1.5, 2R2.5, 3L1.5, 3L2.5, 3M1,
3M2, 3M3, 3R1.5, 3R2.5, 4L1.5, 4L2.5, 4M1, 4M2, 4M3, 4R1.5, 4R2.5,
5M1, 5M2, 5M3. They are arranged from brightest color to darkest
color.
[0134] The 3 Shape Trios intraoral scanner's color readings were
three-dimensional values. For comparison, the 29 3-D readings of
VITA shade guide were represented by numerical color grade from 1
to 29. In Table 9, 1 represents the brightest color (0M1) and 29
represent the darkest color (5M3) correspondingly.
TABLE-US-00009 TABLE 9 Three-D Readings vs. Color Grades 3-D
reading 0M1 0M2 0M3 1M1 1M2 2L1.5 2L2.5 2M1 2M2 2M3 Color grade 1 2
3 4 5 6 7 8 9 10 3-D reading 2R1.5 2R2.5 3L1.5 3L2.5 3M1 3M2 3M3
3R1.5 3R2.5 4L1.5 Color grade 11 12 13 14 15 16 17 18 19 20 3-D
reading 4L2.5 4M1 4M2 4M3 4R1.5 4R2.5 5M1 5M2 5M3 Color grade 21 22
23 24 25 26 27 28 29
[0135] 3-D readings are arranged from lightest color (0M1) to
darkest color (5M3); the corresponding numbers also represent the
colors from lightest (1) to darkest (29).
[0136] The tooth specimens were mounted onto the V-White cross
brushing machine equipped with a soft nylon-filament (Oral B soft
toothbrush) and adjusted a tension of 150 g upon the enamel
surface.
[0137] Sample group: Sample toothpaste (Example 1, formulation 3,
stored for 6 month before test) was made into slurry consisting of
25 g of toothpaste mixed with 50 mL of de-ionized water.
[0138] Comparative group: An ADA reference material was used as a
comparison tooth surface cleaning reference. The reference
comparison slurry consisted of 10 g ADA standard Calcium
pyrophosphate mixed with 50 mL of a mixture of 0.5% carboxymethyl
cellulose and 10% glycerin in water.
[0139] The specimens of the Sample group were brushed with the
slurry of the sample toothpaste and the specimens of the
Comparative group were brushed with slurry of ADA Calcium
pyrophosphate. At each brushing cycle, the specimens were brushed
for 800 double strokes per min. for three min. with the
corresponding slurry (the Sample toothpaste slurry or the ADA
Calcium pyrophosphate slurry). The slurries were replaced with new
slurry at each of the 3 min intervals. A total of 14 cycles were
run.
[0140] A computer color matching (CCM) system of 29 shade tabs from
the VITAPAN 3D-Master shade guide was used to match the specimen
readings from the 3 Shape-Trio readings of the 24 specimens. The 29
shades of the VITA shade guide 3-D values are: 0M1, OM2, OM3, 1M1,
1M2, 2L1.5, 2L2.5, 2M1, 2M2, 2M3, 2R1.5, 2R2.5, 3L1.5, 3L2.5, 3M1,
3M2, 3M3, 3R1.5, 3R2.5, 4L1.5, 4L2.5, 4M1, 4M2, 4M3, 4R1.5, 4R2.5,
5M1, 5M2, 5M3. They are arranged from brightest color to darkest
color.
[0141] The before and after color readings of the sample group are
displayed in Table 10.
TABLE-US-00010 TABLE 10 Sample Group Color Readings Before and
After T1 T2 T3 T4 T5 T6 T7 T9 T10 T12 T13 T14 bef. 3D 5M2 5M2 5M2
5M1 5M2 5M2 5M1 5M3 5M1 5M1 5M3 5M1 aft. 3D 1M2 2M1 1M2 1M1 1M1 1M2
1M1 2M1 1M1 1M2 2M1 0M2 bef. L* 59.48 59.48 59.48 58.55 59.48 59.48
58.55 60.51 58.55 58.55 60.51 58.55 aft. L* 78.43 72.94 78.43 76.48
76.48 78.43 76.48 72.94 76.48 78.43 72.94 79.59 bef. N 28 28 28 27
28 28 27 29 27 27 29 27 aft. N 5 8 5 4 4 5 4 8 4 5 8 2 3D:
three-dimensional value; L*: L* value; N: numerical color grade
[0142] The before and after color readings of the comparative group
are displayed in Table 11.
TABLE-US-00011 TABLE 11 Comparative Group Color Readings Before and
After T8 T11 T15 T16 T17 T18 T19 T20 T21 T22 T23 T24 bef. 3D 5M2
5M2 5M2 5M2 5M1 5M1 5M2 5M2 5M1 5M1 5M1 5M3 aft. 3D 5M2 5M1 4M2 5M2
4M1 5M1 5M1 5M1 5M1 4M1 5M1 5M1 bef. L* 59.48 59.48 59.48 59.48
58.55 58.55 59.48 59.48 58.55 58.55 58.55 60.51 aft. L* 59.48 58.55
64.16 59.48 64.22 58.55 58.55 58.55 58.55 64.22 58.55 58.55 bef. N
28 28 28 28 27 27 28 28 27 27 27 29 aft. N 28 27 23 28 22 27 27 27
27 22 27 27 3D: three-dimensional value; L*: L* value; N: numerical
color grade
[0143] Paired t-Tests were performed to evaluate the results.
Statistical analysis data is displayed in Table 12.
TABLE-US-00012 TABLE 12 Paired t-Tests Paired Differences 95%
Confidence Std. Std. interval of 2-tailed devi- Error difference
Signi- mean ation mean Lower Upper t df ficance Pair 1 S bef. vs. C
bef. 0.086 0.648 0.187 -0.326 0.498 0.495 11 0.655 Pair 2 S bef.
vs. S aft. -17.240 2.384 0.688 -18.755 -15.725 -25.048 11 0.000
Pair 3 C bef. vs. C aft. -0.939 2.527 0.730 -2.545 0.667 -1.287 11
0.224 Pair 4 S aft. vs. C aft. 16.387 3.917 1.131 13.898 18.875
14.494 11 0.000 S: Sample group; C: Comparative group; bef.: before
test; aft.: after test.
[0144] Results from paired t-test showed:
[0145] The colors of the test group and the comparative group had
no difference prior to the tests (P>0.05), which meant the
Sample groups were comparable.
[0146] The before and after color differences for the Sample groups
were statistically significant (P<0.05), which meant the Sample
composition was effective in reducing biofilm.
[0147] The before and after color differences for the Comparative
group were statistically significant (P<0.05), which meant the
abrasive force of the ADA Calcium pyrophosphate slurry was also
effective for reducing biofilm.
[0148] However, the significant differences in color change
(P<0.05) between the Sample group and the Comparative group
clearly demonstrated the superior efficacy of the Sample
composition.
* * * * *